Recent work from our laboratory indicates that the size distribution and structure of the zymogen granule of the pancreas may vary with physiological state. The zymogen granule has generally been assumed to be constant in size and of unitary structure. However, granules in the newborn are extremely large and undergo dramatic decreases in size during the first weeks of postnatal life. A similar but less dramatic decrease in granule size is seen in adult rats with feeding after a prolonged fast. We intend to analyze the zymogen granule size distribution during the first three weeks of postnatal life and in the adult pancreas after feeding or stimulating with a cholinergic drug. We also plan to measure the turnover of zymogen granules in the postnatal pancreas and correlate the turnover with changes in size distribution. Changes in granule size have not been appreciated in the past. The evidence and character of dynamic changes in granule size and structure may have an important impact on our understanding of the way in which the pancreas secretes digestive enzymes. We have also found that the zymogen granule has a solid state structure defined by interactions between the digestive enzymes, the granule membrane, and possible structural elements. We are interested in the factors responsible for formation of intragranular aggregates and plan to inhibit aggregation of zymogen granule components using competitive inhibitors in order to identify and localize binding sites. These studies bear upon the mechanisms of transport of secretory products in general and particularly proteins, and compare and test current hypotheses regarding these mechanisms.